We propose to continue work that began in 1967 to elucidate mechanisms by which drugs of abuse (amphetamine and congeners, cocaine, methylphenidate, indoleamine and phenylethylamine hallucinogens, opiates, and centrally active adrenergic and cholinergic agents) alter the regulatory properties of regional brain tyrosine (TOH) and tryptophan (TPOH) hydroxylases, enzymes modulating the biosynthesis of norepinephrine, dopamine, and serotonin in their respective systems. Our current focus is a complex, amphetamine-sensitive (adrenergic/cholinergic?) interactive mechanism involving a) regional regulation of tetrahydrobiopterin (BH4) levels; b) the relationship between those levels and the conformational stability of TOH and TPOH; and c) the role of the enzymes' conformational stability in regulating their physical/functional coupling with quinonoid dihydropteridine reductase (QDPR), which coupling affects levels of amine-relevant (BH4). We shall examine the effects of drugs on allosteric, variational, and pre-incubation enzyme inactivation kinetics in vitro in relation to their effects on regional levels of (BH4) after administration to rats in vivo. Extending both dose and time beyond the dose-response asymptote, we shall explore the possibility suggested by early findings that, with respect to some measures psychopharmacological ligands elicit nonlinear, cyclic dose-response functions. Decreases in (BH4) induced by amphetamine as well as certain sacrifice procedures require hours to days for recovery. We hypothesize an amphetamine-induced decompensation of the BH4 maintenance system in which drug-induced instabilities in macromolecular conformations lead to partial uncoupling of TOH/QDPR or TPOH/QDPR, decreasing regional (BH4) (which serves as a ligand modulating conformational stability in the mixed-function oxygenases themselves), thus leading to further fluctuations in kinetic phenomena. Preliminary evidence that low (BH4) and behavioral stereotypy may be related leads to the suggestion that progressive sensitivity to the behavioral effects of repeated administration of amphetamine may involve such a mechanism.